An immune response occurs only if a T lymphocyte has been able to recognize the foreign antigen in association with a self molecule encoded in the major histocompatibility complex (MHC). These molecules expressed on antigen-presenting cells are the polymorphic class II MHC antigens. Most foreign antigens must be processed in order to bind to MHC molecules. How the processed peptides are generated and where they interact with MHC molecules is largely unknown. The aim of this project is to define the function of the different human class II antigens in their interaction with T cells and the requirements for class II-restricted processing and presentation of viral antigens. Three isotypic class II antigens exist in man: HLA-DR, -D, and -DP. Two additional transcribed genes have been identified by cDNA cloning and sequencing: DNQ and DO beta. A novel type of alternative splicing has been found in DN alpha. The alternatively spliced RNA encodes a short protein totally unrelated to the class II DN alpha chain, except for a shared signal sequence. The interaction between a class II MHC molecule and a specific T cell is complex because it involves (i) an immunogenic peptide, (ii) an antigen-specific T-cell receptor (TCR), and (iii) the CD4 molecule expressed on the T cell. In order to dissect these interactions an assay has been developed that measures a functional CD4-class II interaction in the absence of a TCR-class II interaction. Using this assay, it has been demonstrated that both HLA-DR and -DP antigens can interact with CD4 and that the site on CD4 involved in this interaction is probably distinct from that to which HIV binds. The cytotoxic T lymphocyte (CTL) response to measles virus is primarily MHC class II-restricted. Transfected cells expressing HLA-DR antigen and cytoplasmic viral antigens were efficiently lysed by measles virus-specific CTLs, demonstrating that endogenously synthesized cytoplasmic proteins can be presented by class II MHC antigens.